Purpose: Antiretroviral therapy can provide potent suppression of plasma and lymph node HIV RNA. Although the kinetics of a second phase of plasma HIV RNA decay have suggested that the reservoir of chronically infected cells may have a limited life span, it remains uncertain whether antiretroviral therapy alone can significantly diminish this reservoir. Current estimates speculate that complete suppression of HIV replication for several years may be needed to achieve meaningful reduction or eradication of the reservoir. We hypothesize that cytoreductive therapy in conjunction with complete suppression of viral replication to prevent reinfection of repopulating lymphoid cells may help expedite the elimination of this reservoir. Methods This is a single-center, phase I/II individual dose escalation study of the effect of cytoreductive chemotherapy combined with aggressive antiretroviral therapy on lymph node HIV DNA (viral load) in ten treatment-naive HIV-infected male and female subjects with CD4 T-cell counts >300 cells/mm3. Eligible subjects will enter Step 1 and will receive up to 16 weeks initiation of aggressive antiretroviral therapy (HAART; highly active antiretroviral therapy). Those who demonstrate two undetectable viral load measurements (plasma HIV RNA measurements <200 copies/ml) in samples collected at least two weeks apart will enter Step 2 and will be randomized to receive antiretroviral alone or antiretroviral therapy plus cytoreductive chemotherapy (cyclophosphamide). The cytoreductive chemotherapy will be given as three single doses over a 12-week period and will be dose escalated two times. All three doses will be administered in the Duke University General Clinical Research Center (GCRC). Pharmacokinetic (PK) studies will be performed in the GCRC to determine potential PK interactions between cyclophosphamide and the antiretroviral agents. Subjects will be followed for a total of 52 weeks after randomization to Step 2 (Cyclophosphamide +HAART or HAART alone). The primary endpoints are the difference in the change in integrated viral DNA in lymph nodes from baseline to week +18 between the two treatment groups and the safety of the antiretroviral therapy plus cytoreductive chemotherapy as measured by the absence of any significant or serious toxicities. To study the potential dose response effect on lymphoid HIV reservoirs and to carefully monitor for potential toxicities, cytoreductive chemotherapy will be administered as a dose escalation with one hour IV infusions of cyclophosphamide starting at 750 mg/m2, followed by 1.2 g/m2 and 1.8 g/m2 at 6 week intervals (3.75 g/m2 total dose). Each of those dosages are below the maximum tolerated dose (MTD) for single dose cyclophosphamide which is 4 g/m2. The HAART regimen will contain the following agents which have all been FDA-approved for the treatment of HIV infection: 1.nelfinavir (Viracept.), 2.d4T (Zerit.), 3. 3TC (Epivir). ACTG 380 continues to screen and enroll subjects. Results: Seven subjects have entered the study, and the first subject will complete the final lymph node biopsy this month. All subjects have tolerated the antiretroviral therapy well; to date all subjects have reached plasma HIV RNA levels by week 24. One subject required a dose plateau in cyclophosphamide; the remaining subjects have developed mild toxicities (< grade 2). One subject developed a lymphocele at the lymph node biopsy site and required re-operation. Data have not yet been analyzed, presented or published. In the next calendar year, all subjects should complete this trial. Significance: This study addresses the critically important question of how to eradicate HIV in infected patients.